To study the effect of atrial natriuretic peptide (ANP) on vascular permeation of albumin in the fetus, ANP (167–600 ng/min) was infused into eight ovine fetuses and saline vehicle was infused into eight twin controls (gestational age 127 ± 3 d) over a 50-min period. Using two different radiolabeled albumin markers, we determined the tissue to blood isotope ratio (TBIR), an index of albumin permeation, and the albumin clearance. Although ANP had no hemodynamic effect, a marked increase in the hematocrit was observed in ANP-infused fetuses compared with initial values (0.37 ± 0.04vs0.42 ± 0.04, p < 0.005) but was unchanged in the twin fetuses receiving saline vehicle (0.35 ± 0.03versus0.35 ± 0.02). TBIR and albumin permeation were increased in combined tissues of ANP-infused fetuses compared with saline controls (TBIR: 1.49 ± 0.58versus1.29 ± 0.3, p < 0.001; albumin clearance: 1091 ± 1279versus827 ± 1464 mL/g/min, p < 0.01). In individual tissues, TBIR was significantly increased in skin (2.88 ± 0.67versus1.55 ± 0.35, p < 0.02), muscle (1.6 ± 0.27 versus 1.24 ± 0.26, p < 0.02), adrenal (1.33 ± 0.10 versus 1.13 ± 0.15, p < 0.02), bone (1.67 ± 0.45versus1.20 ± 0.40, p < 0.02), kidney (1.52 ± 0.25versus1.24 ± 0.26, p < 0.03), and gut (1.69 ± 0.20versus1.39 ± 0.34, p < 0.03). Albumin clearance was higher in most tissues but reached statistical significance only in skin (2135 ± 944versus775 ± 847 mL/g/min, p < 0.05) and bone (1012 ± 1107versus428 ±482 nL/g/min, p < 0.05). We conclude that overall vascular filtration is higher in the fetus than the adult. Infusion of ANP causes fetal hemoconcentration, decreases blood volume, and enhances vascular permeation of albumin in most tissues, particularly fetal skin. We speculate that the cardiac atria, by secreting ANP, participate in blood volume regulation by maintaining a critical balance between the intravascular and extravascular fluid compartments. Dysregulation of the ANP system might result in fetal hydrops.